1. CARDIAC CHANNELOPATHIES
Dr Binjo J Vazhappilly
SR Cardiology
Calicut Medical College

2. Cardiac channelopathies refers to genetic disorders characterized by altered cardiac excitability, in the absence of structural cardiac involvement.
Also known as inherited arrhythmogenic diseases (IADs).
Disorders due to genetic mutation affecting the genes that control the excitability of myocardial cells.

3. Major cardiac channelopathies include
Long QT Syndrome
Brugada syndrome
CPVT
Short QT syndrome

4. Webster and Berul circulation 2013;127:126-140

5. Long QT Syndrome
LQTS is an IAD characterized by abnormally prolonged QT interval.
13 genes are found to be linked to LQTS till now.
Mutations in 3 genes KCNQ1 (LQT1), KCNH2 (LQT2) and SCN5A (LQT3) accounts for approximately 75% of cases with a strong clinical phenotype.

6. Assumed to be 1/2500 live births .
Prevalence
Assumed to be 1/2500 live births .
In an Italian study ,where ECG was performed in 44,596 infants , 0.07% had a QTc >470 ms and 0.47% had QTc between 451 and 470 ms
Molecular screening showed
disease-causing mutation in
43% of neonates with
QTc >470 ms & 29% of
those with QTc b/w
461 and 470 ms
Schwartz etal
Circulation. 2009;120:

7. CHANNELOPATHY GENE PROTEIN LQT 1 KCNQ1 α-subunit of Iks LQT 2 KCNH2
α-subunit of Ikr
LQT 3
SCN5A
Sodium channel, α-subunit
LQT 4
ANK2
Cellular structural protein
LQT 5
KCNE1
β-subunit of Iks
LQT 6
KCNE2
β-subunit of Ikr
LQT 7
KCNJ2
α-subunit of Ik1

8. CHANNELOPATHY GENE PROTEIN LQT 8 CACNA1C
l-type Ca + channel, α-subunit
LQT 9
CAV3
Plasma membrane structural protein
LQT 10
SCN4B
Sodium channel, β-subunit
LQT 11
AKAP9
Kinase anchoring protein (Yotaio)
LQT 12
SNTA1
Syntrophin α1 (affects sodium current)
LQT 13
KCNJ5
Inwardly rectifying potassium channel, α-subunit

9. Potassium Channel LQTS
Potassium channel derangements account for majority of LQTS cases : Long QT 1, 2, 5, 6, 7 and 13.
IKs : slowly activating delayed rectifier cardiac potassium channel
 subunit is encoded by KCNQ1
β subunit is encoded by KCNE1
Loss of function mutation result in LQT 1 and LQT 5
Ikr : rapid delayed rectifier potassium channel
 subunit encoded by KCNH2
β subunit encoded by KCNE2
Loss of function mutation result in LQT 2 and LQT 6.

10. IKI : another inwardly rectifying K+ channel
encoded by gene KCNJ2
Loss of function mutation result in LQT 7 (Tawil-Anderson syn)
KCNJ5 mutation which is a loss-of-function mutation in an inwardly rectifying potassium channel result in LQT 13

11. Sodium channel LQTS
 subunit of sodium channel is encoded by SCN5A and β subunit encoded by SCN4B.
Gain of function mutations in SCN5A produce LQT3.
Mutations in SCN4B produce LQT10.

12. Molecular basis for long QT syndrome
Topol EJ, Califf RM et al

13. Pathophysiology of LQTS
Prolonged repolarization results fm net reduction in outward current, due to ↑ in inward Na + or Ca + current, ↓ in outward K+ current or both resulting in long QT interval.
Fast heart rate preceding TdP in LQT1 postulate delayed afterdepolarizations (DADs) as its arrthymogenic mechanism.
Increased Ca+ loading in parallel with QT prolongation, facilitate DADs and DAD-dependent TdP.
Pause-dependent TdP is triggered by early afterdepolarizations (EADs).
Pause leads to enhanced Ca+ release from intracellular stores and activate Ca+ dependent transmembrane currents.

14. Initiation of arrhythmia in LQTS
Non-pause dependent
torsade de pointes
Mainly in LQT1
Pause dependent
torsade de pointes
Mainly in LQT2

15. Clinical features May be asymptomatic
Symptomatic pts present with palpitations, presyncope, syncope or cardiac arrest.
Neuronal deafness is associated with Jervell and Lange-Nielsen syndrome
In a study on 287 pts , 61% were symptomatic : 9% presented with a cardiac arrest, 26% with syncope ,10% with seizures , 6% had presyncore or palpitation
67% had symptoms related to exercise, 18% had symptoms during exercise and with emotion, 7% with emotion alone, 3% with loud noise and exercise and 2% with anesthesia.
A Garson, M Dick et al Circulation. 1993;87:

16. Triggers of arrhythmia
Triggers include exercise, noise, emotion, sudden wakening from sleep by noise , swimming or diving.
Swimming and exertion-induced cardiac events are strongly associated with LQT1.
Auditory triggers and events
during postpartum period
occur in pts with LQT2.
Events occurring during periods of
sleep or rest are most common in
LQT3.

17. Triggers of LQTS
Schwartz et al

18. Jervell and Lange-Nielsen syndrome
Autosomal recessive variant of long QT syndrome.
Due to homozygous or compound heterozygous mutations on either the KCNQ1 or KCNE1 genes.
Pts also suffer from congenital deafness.
Most severe of major variants of LQTS.
90% have cardiac events, 50% become symptomatic by
age of 3 yrs and their average QTc is markedly prolonged (557± 65 ms)

19. Event-free survival comparing Jervell and Lange-Nielsen syndrome pts with other long-QTS

20. Timothy syndrome / LQT8
Mutations in CACNA1C, encoding voltage-gated calcium channel results in Timothy syndrome or LQT8.
Rare and extremely malignant variant.
Pts had marked QT prolongation and associated syndactyly .
Presents with 2:1 atrioventricular block and macroscopic T-wave alternans.
Among 17 children reported by Splawski et al, 10 (59%) died at a mean age of 2.5 yrs.

21. ECG in LQTS
QTc values exceeding 440 ms (in males) and 460 ms (in females) are considered abnormal .
LQT1 is associated with a broad-based T wave.
LQT2 with low-amplitude notched or
biphasic T wave.
LQT3 with long isoelectric segment followed
by a narrow-based T wave.

22. LQTS : Diagnostic Criteria
Score
≤1 point: low probability
1.5–3 points: intermediate probability
≥3.5 points: high probability.
Schwartz et al
Circ Arrhythm Electrophysiol. 2012;

23. Keating Criteria Asymptomatic with QTc > 470 ms or Typical symptoms with QTc ≥ 450 ms
Sensitivity and specificity of
QTc duration alone ,
Schwartz score and
Keating criteria
Nynke Hofman, Arthur A.M. Wilde et al
EHJ

24. Risk stratification
Risk of a 1st cardiac event in pts younger than 40 years of age in the absence of any LQTS active treatment

25. Treatment
All LQTS pts with h/o syncope and asymptomatic individuals with definite QT prolongation should be treated withβ-blockers
Drugs used are Propranolol ( 2-4 mg/kg/d),
Nadolol (1-2.5 mg/kg/d)
Metoprolol (2-4 mg/kg/d)
Dose titration done with a target of 25% to 35% reduction of maximal heart rate attained on therapy.
Left Cardiac Sympathetic Denervation may be considered in symptomatic patients even after betablocker therapy.

26. Treatment
ICD implantation along with β -blockers is recommended for LQTS patients with previous cardiac arrest or who are experiencing syncope and/or VT while receiving beta blockers.
Permanent pacing is indicated for sustained pause-dependent VT, with or without QT prolongation.
Avoid competitive sports, QT-prolonging drugs and lowered K+ levels .

27. β-blocker therapy in LQTS
β-blocker therapy results in 42% to 78% reduction of aborted cardiac arrest or sudden cardiac death.
Pts on β-blockers still have risk of sudden death.
In a study , no. of cardiac events before initiation of β-blocker therapy was 0.97 events /pt/yr which decreased to 0.31 after initiation of therapy .
β-blocker is most efficacious in LQT1 and less effective in LQT3.
In LQT3, combination of mexiletine with a noncardioselective β-blocker (propranolol ) is used .

28. Brugada Syndrome
Characterized by peculiar ECG pattern of ST-segment elevation in leads V1 to V3 and incomplete or complete RBBB in the absence of signs of acute MI.
Autosomal dominant disorder with variable expression
More common in men than in women.
Usually diagnosed in adulthood ( Avg age at diagnosis is 41 yrs).

29. Genes Involved in Brugada
CHANNELOPATHY
GENE
CHANNEL/PROTEIN
Effect
BrS 1
SCN5A
Cardiac sodium channel  subunit
↓ Na+ current
BrS 2
GPD1L
Glycerol-6-phosphate dehydrogenase
↓ Na+ current
BrS 3
CACNA1C
L-type calcium channel  subunit
↓ Ca2+ current
BrS 4
CACNB2
L-type calcium channel β subunit
BrS 5
SCN1B
Cardiac sodium channel β1 subunit
BrS 6
KCNE3
Transient outward current β subunit
↑ K+ Ito current
BrS 7
SCN3B
Cardiac sodium channel β3 subunit

30. ECG patterns
Type-1 ≥ 2-mm J-point elevation, coved type ST-T segment elevation and inverted T-wave in leads V1 and V2. Type-2 ≥ 2-mm J-point elevation, ≥ 1-mm St segment elevation, saddleback ST-T segment and a positive or biphasic T-wave. Type-3 Same as type 2, except that the ST-segment elevation is <1 mm.

31. Placement of precordial
leads in higher intercostal spaces can unmask the
Brugada ECG pattern

32. Pathophysiology
Debate is still going on whether pathophysiology is due to repolarization or depolarization disorder.
Repolarization hypothesis by Yan and Antzelevitch
Transmembrane voltage gradient b/w RV epicardium and endocardium due to heterogenous loss of AP dome in epicardium and not in endocardium.
Heterogeneity of transmembrane voltage potentials result in phase 2 reentry and triggered VF.

33. Pathophysiology Yan and Antzelevitch- Faulty repolarization
Cardiovascular Research 67 (2005) 367 – 378

34. Depolarization hypothesis
In BS pts RVOT endocardium shows activation slowing and is the last to depolarize.
Delay in AP of RVOT causes an electrical gradient from more positive RV to RVOT, leading to ST-elevation in right precordial leads.
When RVOT depolarizes later (during repolarization of RV), this gradient is reversed and net current flows towards RV, resulting in a negative T-wave in right precordial leads.

35. Depolarization Hypothesis
conduction delay in RVOT
Cardiovascular Research 67 (2005) 367 – 378

36. Clinical Presentation
Clinical spectrum ranges from asymptomatic to SCD.
Patients may present with late onset of VF, despite having abnormal ECG pattern for decades.
Syncope or seizures may occur due to self-terminating VF episodes.
Agonal respiration and difficulty in arousal at night also may be due to self-terminating VF episodes.
Majority of BS pts are young, b/w 20 and 40 yrs of age at presentation.

37. Brugada : Diagnostic criteria
Appearance of type 1 ST segment elevation (coved type) in > 1 rt precordial lead (V1 - V3) in the presence or absence of a sodium channel blocker, plus at least one of the following:
Documented ventricular fibrillation.
Polymorphic ventricular tachycardia (VT).
Family h/o sudden cardiac death at less than 45 years of age.
Family h/o of type 1 Brugada pattern ECG changes.
Inducible VT during electrophysiology study.
Unexplained syncope.
Nocturnal agonal respiration .
Type 2 and type 3 ECG are not diagnostic of Brugada syndrome
Second Consensus Conference : Europeon Heart Rhythm Society

38. Brugada pattern : Pts with typical ECG features who are asymptomatic and not having other clinical criteria.
Brugada syndrome : Pts with typical ECG features and clinical criteria (who have experienced sudden cardiac death or a sustained ventricular tachyarrhythmia or who have one or more of the other associated clinical criteria )

39. Drug challenge
Done in pts with resting ECG type 2 or 3 Brugada pattern and having family h/o sudden cardiac death at < 45 yrs and/or a family h/o type 1 Brugada pattern ECG
Drugs used
Flecainide : 2 mg/kg over 10 min iv or 400 mg PO
Procainamide : 10 mg/kg over 10 min iv
Ajmaline : 1 mg/kg over five minutes iv
Pilsicainide : 1 mg/kg over 10 minutes iv

40. Drug challenge
Indications for termination of the drug challenge include:
Development of a diagnostic type 1 Brugada pattern
≥2 mm increase in ST segment elevation in pts with type 2 Brugada ECG pattern
Development of ventricular premature beats or other arrhythmias
Widening of the QRS ≥30 percent above baseline

41. Risk stratification

42. Treatment
ICD is the only effective treatment to reduce mortality in BrS
ICD indication
Class 1
BrS pts with previous cardiac arrest.
Class IIa
BrS pts with spontaneous pattern with h/o syncope.
BrS pts with documented VT that has not resulted in cardiac arrest.
Drugs : Quinidine or amiodarone may be used for pts not willing for ICD / reduced life expectancy.
Electrical storm: Isoprotenol or Quinidine may be used.

43. Short QT Syndrome Rare condition with short-QT interval (<320 ms).
Presents symptomatically with recurrent syncope, sudden cardiac death and atrial fibrillation.
Mutations in 6 different genes (3 gain of function and 3 loss of function) are identified .

44. Genes in SQTS IKs CHANNELOPATHY GENE CHANNEL /PROTEIN SQT 1 KCNH2 IKr
KCNQ1
IKs
SQT3
KCNJ2
IK1
SQT4
CACNA1C
l-type ca+ channel, α-subunit
SQT5
CACNB2
l-type ca+ channel, β-subunit
SQT 6
CACNA2D1
l-type calcium channel subunit

45. Basis of Arrhythmogenesis
Abbreviation of action potential in SQTS is heterogeneous with preferential abbreviation of either epicardial or endocardial cells as compared with sub-endocardial M cells, resulting in dispersion of repolarization .
Dispersion of repolarization serves as substrate for initiation and maintenance of reentry.

46. 62 % (18 out of 29) were symptomatic
In a case series1 of 29 pts
62 % (18 out of 29) were symptomatic
Cardiac arrest – 34 %(initial symptom in 28%)
Palpitations – 31 %
Syncope – 24 %
Atrial fibrillation – 17 %
Electrocardiographic findings
Abnormally short QT interval
Absence of ST segment
Tall and peaked T waves
Prolonged Tpeak-Tend interval and Tpeak-Tend/QT ratio.
1.Carla Giustetto, Fernando Di Monte etal EHJ(2006) 27, 2440–2447

47. Proposed Diagnostic Criteria: SQTS
Michael H. Gollob, MD, Calum J. Redpath et al JACC Vol. 57, No. 7, 2011

48. Management
ICD implantation recommended for both primary and secondary prevention of SCD in pts with SQTS.
Pharmacological therapy with QT prolonging drugs.
Quinidine is recommended in SQT1 syndrome.
Disopyramide and amiodarone are also shown to prolong QT in SQTS pts.

49. Catecholaminergic polymorphic ventricular tachycardia (CPVT)
CPVT is a disorder of intracellular calcium handling causing adrenergic-dependent arrhythmias and sudden death.
Pts have normal resting ECG and develop ventricular ectopy progressing to bidirectional or polymorphic VT during exercise or catecholamine infusion .
Pts present with life-threatening VT or VF occurring during emotional or physical stress.
Affected patients may have a family h/o juvenile sudden death or stress-induced syncope .
CPVT can also present sporadically following a de novo mutation.

50. Genetic basis
Mutations in 2 genes are identified : ryanodine receptor gene (RyR2) and calsequestrin 2 gene (CASQ2).
RyR2 mediates release of Ca+ from SR which is is required for myocardial contraction.
RyR2 mutation result in Autosomal Dominant form of CPVT
Calsequestrin 2 protein is a protein in sarcoplasmic reticulum which binds large amounts of calcium.
CASQ2 mutation result in Autosomal Recessive form of CPVT.

51. Mechanism for Arrhythmogenesis
Delayed after depolarization (DAD) dependent triggered activity.
Mutant ryanodine receptor is leaky and it releases excess of calcium during diastole.
This activates sodium-calcium exchanger that extrudes calcium ions out from the cell.
This generates a net inward current results in DAD.
When large enough, DADs trigger extrasystolic action potential.

52. Mechanism for Arrhythmogenesis

53. Treatment Avoiding competitive sports
Beta blockers for all pts with spontaneous or documented stress-induced ventricular arrhythmias.
For survivors of cardiac arrest or pts with syncope or sustained VT or VF despite therapy with beta blockers, ICD is recommend.
Flecainide or verapamil may be given for pts who are symptomatic with ICD and beta blockers .
Left sympathetic denervation for pts who remain symptomatic after maximal medical therapy.

54. Other Channelopathies
Arrhythmogenic Right Ventricular Cardiomyopathy ( ARVC )
Subset of ARVC is caused by defects in cardiac ryanodine receptor (RyR2)
May represent a variant of CPVT rather than a subset of CPVT .
Majority are caused by defects in desmosomal proteins
PKP2 encoding plakophilin 2 : most common
DSP encodes desmoplakin
DSG2 encodes desmoglein 2
Hallmark of ARVC is fibrofatty replacement of the myocardium
Arrhythmias may precede histological evidence of disease

55. Familial AF Familial clustering may occur in AF
Account for a minority of pts with lone AF
KCNH2
IKr
↑ outward K+ current
KCNQ1
IKs
KCNJ2
IK1
GJA5
Gap-junction protein connexin 40
Impared conduction

56. Sinus Node Dysfunction and Conduction Defects
Mutations of HCN4 gene which codes for cardiac pacemaker current (If) results in sinus node dysfunction.
Other mutation which are associated with conduction defects are SCN5A , NKX2.5 and GATA 5

57. Summary
Cardiac channelopathies represent a group of disorders with inherited arrhythmogenic potential and structurally normal heart.
Majority are due to mutations in genes encoding Na+ , K+ , Ca + channels of heart.
In LQTS arrhythmia is triggered by exercise , emotion or noice.
Brugada syndrome is diagnosed by type 1 Ecg and documented event.
Beta blockers are useful in LQT1 and CPVT.
ICD is indicated in survived cardiac arrest pts and in high risk patients.

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